ORGANIC LETTERS
The Heck Reaction in Ionic Liquids: A Multiphasic Catalyst System
1999 Vol. 1, No. 7 997-1000
Adrian J. Carmichael,† Martyn J. Earle,* John D. Holbrey,† Paul B. McCormac, and Kenneth R. Seddon‡ School of Chemistry, The Queen’s UniVersity of Belfast, Stranmillis Road, Belfast, Northern Ireland, U.K., BT9 5AG
[email protected] Received July 1, 1999
ABSTRACT
Heck coupling of aryl halides or benzoic anhydride with alkenes can be performed with excellent yields in room-temperature ionic liquids, which provide a medium that dissolves the palladium catalyst and allows the product and byproducts to be easily separated. Consequently, the catalyst and ionic liquid can be recycled and reused.
The Heck reaction is of major importance in synthetic organic chemistry, as a carbon-carbon bond-forming reaction.1 It is often used to functionalize aromatic rings and as an alternate to the Friedel-Crafts reaction.2 The Heck reaction usually involves the interaction of an aromatic halide3 or anhydride4 with an alkene, in the presence of a palladium catalyst at typically a 1-2 mol % concentration, to give an aryl alkene. The reaction normally requires a base to be present,5,6 particularly in the reactions of aryl halides (but not anhydrides).4 A major problem with the Heck reaction is that the palladium catalyst is often lost at the end of the
reaction.6 Hence, a process for recycling the catalyst system is of importance. Room-temperature ionic liquids have been used to great effect as solvents for a number of reactions, for example, Friedel-Crafts reactions,7 isomerizations of fatty acid derivatives,8 dimerization reactions of alkenes,9 Diels-Alder reactions,10 and hydrogenation reactions.11 Ionic liquids such as 1-butyl-3-methylimidazolium hexafluorophosphate12 ([bmim][PF6]) have a particularly useful set of properties, being virtually insoluble in water and alkanes but readily dissolving many transition metal catalysts.13 Such biphasic
† The QUESTOR Centre, The Queen’s University of Belfast, Stranmillis Road, Belfast, Northern Ireland, U.K., BT9 5AG. ‡ The QUILL Centre, The Queen’s University of Belfast, Stranmillis Road, Belfast, Northern Ireland, U.K., BT9 5AG. (1) (a) Dieck, H. A.; Heck, R. F. J. Org. Chem. 1975, 40, 1083. (b) Kim, J.-I. I.; Patel, B. A.; Heck R. F. J. Org. Chem. 1981, 46, 1067. (c) Bender, D. D.; Stakem, F. G.; Heck, R. F. J. Org. Chem. 1982, 47, 1278. (2) Olah, G. A. Friedel-Crafts Chemistry; Wiley-Interscience: New York, 1973. (3) Namyslo, J. C.; Kaufmann, D. E. Synlett 1999, 114. (4) Stephan, M. S.; Teunissen, A. J. J. M.; Verzijl, G. K. M.; Vries, J. G. de Angew. Chem. Int. Ed. Engl. 1998, 37, 662. (5) Jeffery, T.; J. Chem. Soc., Chem. Commun. 1984, 1287. (6) Shaughnessy, K. H.; Hamann, B. C.; Hartwig, J. F. J. Org. Chem. 1998, 63, 6546.
(7) Adams, C. J.; Earle, M. J.; Roberts, G.; Seddon, K. R. Chem. Commun. 1998, 2097. (8) Adams, C. J.; Earle, M. J.; Hamill, J.; Lok, C. M.; Roberts, G.; Seddon, K. R. World Patent WO 98 07679, 1998. (9) (a) Ellis, B.; Keim, W.; Wasserscheid, P. Chem. Commun. 1999, 337. (b) Einloft, S.; Olivier, H.; Chauvin, Y. U.S. Patent US 5550306, 1996. (10) Earle, M. J.; McCormac, P. B.; Seddon, K. R. Green Chem. 1999, 1, 23. (11) (a) Fisher, T.; Sethi, A.; Welton, T.; Woolf, J. Tetrahedron Lett. 1999, 40, 793. (b) Adams, C. J.; Earle, M. J.; Seddon, K. R. Chem. Commun. 1999, 1043. (12) Huddleston, J. G.; Willauer, H. D.; Swatloski, R. P.; Visser, A. E.; Rogers, R. D. Chem. Commun. 1998, 1765. (13) Dullius, J. E. L.; Suarez, P. A. Z.; Einloft, S.; De Souza, R. F.; Dupont, J.; Fischer, J.; De Cian, A. Organometallics 1998, 17, 815.
10.1021/ol9907771 CCC: $18.00 Published on Web 09/16/1999
© 1999 American Chemical Society
Figure 1. A triphasic mixture of [bmim]2[PdCl4] and P(o-tol)318 in [bmim][PF6] (lower layer), water (middle layer), and cyclohexane (top layer).
ionic liquid systems have been used to enable simple extraction of products.14 Furthermore, if benzoic anhydride is used as a source of aryl moiety, then a base is not required for the reaction (the byproduct in this case is an aryl carboxylic acid which can be recovered at the end of the reaction and converted back to an anhydride).4 We have found that the Heck reaction can be performed in a number of low melting point N,N′-dialkylimidazolium or N-alkylpyridinium ionic liquids with halide, hexafluorophosphate, or tetrafluoroborate anions. For our work, we concentrated on using salts with a limited number of anions and cations, so that a correlation between reactivity in the
Heck reaction and structural differences in the salts could be determined. For the cation, 1-butyl-3-methylimidazolium ([bmim]), 1-pentyl-3-methylimidazolium ([pmim]), or Nhexylpyridinium ([C6py]) species were chosen.15 As mentioned above, the high solubility of both [bmim]2 [PdCl4]13 and [Pd(OAc)2(PPh3)2] in ionic liquids and their low solubility in organic solvents (such as toluene or hexane) enables the products of the reaction to be separated from the ionic liquid and catalyst by solvent extraction with an organic solvent or by distillation from the reaction vessel. Furthermore, if a hydrophobic ionic liquid is chosen (e.g. [bmim][PF6] or [C6py][BF4]), then water can also be used
(14) (a) Bader, A.; Arlt, D.; Seng, F. E.U. Patent EP 0 459 258, 1991. (b) Blanchard, L. A.; Hancu, D.; Beckman, E. J.; Brennecke, J. F. Nature 1999, 399, 28.
(15) (a) Gordon, C. M.; Holbrey, J. D.; Kennedy, A. R.; Seddon, K. R. J. Mater. Chem. 1998, 8, 2627. (b) Holbrey, J. D.; Seddon, K. R. J. Chem. Soc., Dalton Trans. 1999, 2133.
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as an extraction solvent to remove the salt byproducts formed in the reaction. A clear demonstration of this phase behavior is given in Figure 1, where the preferential solubility of the yellow palladium catalyst in the lower ionic phase is clearly apparent. In the Heck reaction of iodobenzene with ethyl acrylate (Table 1), the reaction proceeds smoothly to produce the
Table 1. Heck Reaction of Iodobenzene and Ethyl Acrylate To Give trans-Ethyl Cinnamate in Ionic Liquids with 2 mol % of Pd(OAc)2 entry
ionic liquid
1 2 3 4 5
[C6py]Cl [C6py]Cl [C6py][PF6] [C6py][BF4] [bmim][PF6]
6
[C6py]Cl
7
[C6py]Cl
8 9 10
[pmim]Cl [pmim]Cl [C6py]Cl
temp, time, °C h
yield, %
additive
base
none none none none Ph3P (4 mol %) Ph3P (4 mol %) Ph3P (4 mol %) none none DMF
Et3N NaHCO3 NaHCO3 NaHCO3 Et3N
40 40 80 80 100
24 24 72 72 1
99 98 42 99 95-9919
NaHCO3
40
24
82
NaHCO3
100
24
99
Et3N NaHCO3 NaHCO3
80 100 40
72 24 24
10 19 77
expected trans-ethyl cinnamate in excellent yields.16 For reactions carried out in the chloride salts (entries 1, 2, and 6-10), the N-hexylpyridinium salts give rise to higher yields than the corresponding reactions in imidazolium salts. The addition of a phosphine ligand to the palladium species in the reaction in the pyridinium salt decreased the yield, and a higher reaction temperature was then required to force the reaction to completion (entries 6 and 7). Several authors have reported that a cosolvent such as DMF or N-methylpyrrolidinone (NMP) is required for this reaction;4,17 however we have found that they are not required and can often decrease the yield of the reaction (entry 10). For the reactions carried out in hexafluorophosphate or tetrafluoroborate room-temperature ionic liquids (entries (16) General Procedure for the Heck Reaction in Ionic Liquids. To a round-bottom flask (25 cm3), equipped with a magnetic stirrer flea and reflux condenser, were added 1-butyl-3-methylimidazolium hexafluorophosphate (5.0 g), palladium(II) acetate (0.045 g, 0.20 mmol), and triphenylphosphine (0.105 g, 0.40 mmol), and the mixture was heated to 80 °C for 5 min with stirring to form the ionic liquid solution of the catalyst. A mixture of triethylamine (1.51 g, 15.0 mmol), iodobenzene (2.04 g, 10.0 mmol), and ethyl acrylate (1.25 g, 12.5 mmol) was added, and the mixture was heated to 100 °C for 1 h. Gas chromatographic analysis of the product showed that no iodobenzene was present. The product was extracted from the reaction vessel by the addition of hexane (10 cm3), followed by decanting off a hexane solution of the product. This was repeated three further times. The combined hexane extracts were concentrated on a rotary evaporator, and the product was purified by Kugelrohr distillation. This gave 1.67 g of a colorless oil (yield ) 95%). The spectroscopic properties of this oil were in accordance with those of authentic trans-ethyl cinnamate. (17) (a) Amatore, C.; Broeker, G.; Jutand, A.; Khalil, F. J. Am. Chem. Soc. 1997, 119, 5176. (b) Amatore, C.; Jutand, A. Coord. Chem. ReV. 1998, 180, 511. (18) The catalyst was made by dissolving [bmim]2[PdCl4] (1 equiv) and P(o-tol)3 (2 equiv) in [bmim][PF6] at 70 °C. For background information of this reaction, see: Herrmann, W. A.; Bohn, V. P. W. J. Organomet. Chem. 1999, 572, 141. Org. Lett., Vol. 1, No. 7, 1999
3 and 4), higher reaction temperatures are needed. Of these two anions, the tetrafluoroborate ionic liquid gives higher yields. In contrast to the chloride-based systems, the addition of a phosphine ligand (such as Ph3P) was found to promote the reaction in the imidazolium salt [bmim][PF6] (entry 5). This ionic liquid/catalyst combination can operated under triphasic conditions and give ethyl cinnamate in greater than 95% yield over many reaction cycles,19 without loss of catalytic activity. To test whether less reactive aromatic compounds could reliably undergo the Heck reaction, the reaction of 4-bromoanisole (the relative reactivity in the Heck reaction is as follows: 4-(MeO)C6H4Br < C6H5Br < 4-(CHO)C6H4Br)20 with ethyl acrylate was investigated, in the ionic liquid [bmim][PF6], using triethylamine as the base and a range of Group 15 ligands (Table 2). The reactions were carried out
Table 2. Heck Reaction of 4-Bromoanisole and Ethyl Acrylate To Give Ethyl 4-Methoxycinnamate with Various Group 15 Ligands in [bmim][PF6] with Triethylamine as the Base entry 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27
Group 15 ligand added (4 mol %) none triphenylphosphine tri-o-tolylphosphine
triphenyl phosphite 1,2-bis(diphenylphosphino)ethane27 1,1'-bis(diphenylphosphino)ferrocene27 triphenylarsine triphenylstibine
temp, time, yield, °C h % 100 140 100 140 100 100 140 100 140 100 140 100 140 100 140 100 140
20 18 72 24 4 24 18 24 24 18 24 18 18 12 20 72 24
7 94 65 98 55 65 99 1.5 31
